For many RNA viruses, relatively recent times of origin of
extant viruses are implied by the high rate of substitution
observed in longitudinal studies. However, extrapolation of
short-term rates of substitution can give misleading estimates of
times of divergence. We show here that the common ancestor of
different types of hepatitis C virus (HCV) is older than previously
thought. The rate of HCV sequence change was measured amongst a
cohort of individuals infected following administration of anti-D
immunoglobulin. Virus sequences were obtained in the E1 and NS5B
genes and compared with each other and with sequences from an
infective batch. Taking account of the bias towards synonymous
transition substitutions, the time of divergence of variants of
subtype 1b is estimated to have occurred 70-80 years ago. The
numerous subtypes of HCV are proposed to derive from more than 300
years of endemic infection in certain geographical regions, with
recent spread of some subtypes to other parts of the world.
Estimation of the time of origin of the major HCV genotypes (types
1-6) is problematic, but our data and analogy with other viruses
suggest that divergence occurred at least 500-2000 years ago.